Changes in immune responsiveness during pregnancy are known to occur. We have initiated studies to address what these changes are and how the maternal immune system can avoid an immune response against the fetus despite exposure to foreign fetal antigens. Using a transgenic mouse in which all of the T cells are specific for a male antigen, we can demonstrate that maternal T cells both recognize and are specifically deleted by fetal antigens. Furthermore, the remaining fetal-specific T cells in these pregnant mice are unresponsive as revealed by in vitro assays. Experiments are currently in progress to assess the mechanism by which clonal deletion of fetal-reactive T cells occurs. Initial results reveal a role for fetal-antigen presenting cells in deletion of fetal-reactive cells potentially via fas-ligand/fas interactions. Additional experiments will also address the mechanism by which anergy is induced in the remaining fetal-specific T cells. Future studies will address how these alterations in maternal T cells could effect tolerance induction in mouse models of autoimmune disease and assess what effect maternal tolerance induction during pregnancy will have on the fetus. Autoimmune diseases are prevalent in women during child-bearing years, yet pregnant women are excluded from experimental studies for their treatment because of unknown effects on the fetus and changes in the immune system during pregnancy. Current and pending IND's within the DHP outline experimental treatments for autoimmune diseases by inducing tolerance to specific antigens. There is clearly a need for a preclinical model to assess safety and efficacy of tolerance-inducing products during pregnancy and this project will provide such a model. Also, investigational protocols attempting to induce antigen-specific tolerance often raise safety concerns because it is difficult to predict whether the products will promote tolerance or immunity. While there is much interest in rapidly developing these products for clinical use, many of the safety concerns should be addressed in preclinical models. The system presented here will not only the aid in understanding important aspects of tolerance induction, but will also provide a valuable preclinical model in which to test therapeutic products.